Taste-masking oral dosage form and method of preparing the same

ABSTRACT

A taste-masking oral dosage form. The taste-masking oral dosage form comprises a pharmaceutically active ingredient, and a starch, wherein the pharmaceutically active ingredient is packaged by the starch to form a microparticle. A method of preparing the taste-masking oral dosage form is also disclosed.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a pharmaceutical composition, and morespecifically to a taste-masking oral dosage form and method of preparingthe same.

2. Description of the Related Art

There are various types of oral administrative medicines, such astablets, capsules, granules, powders, syrups and the like. Orallyadministrated medicines, however, suffer from many drawbacks. Forexample, pharmaceutically active ingredients in medicines may leave anunpleasant taste after drug administration.

Tablets and capsules, for example, may be hard to swallow for theelderly or children. Granules and powders may possibly enter therespiratory tract or lungs. Additionally, dosage of syrups, may bedifficult measured, particularly for the elderly or children.

Therefore, many researches regarding taste-masking oral dosage formshave been undertaken recently to provide a new generation rapidlydissolved and safely swallowed tablets, and their dosages can beaccurately measured, particularly can mask bitter. Additionally, tabletsshould possess adequate hardness to facilitate the packaging process.

Several related arts are disclosed in the following. U.S. Pat. No.5,804,212 describes a preparation in which a starch and a nasal drug areblended to form a microparticle to improve nasal absorption. EuropeanPatent No. 230264 discloses an aqueous nasal drug delivery system forvaccines comprising a high molecular weight drug, a gelling agent suchas hydroxyethyl cellulose, and additives such as surfactants orglycerol. The two examples (U.S. Pat. No. 5,804,212 and European PatentNo. 230264) merely cite how to improve drug absorption effects, withoutcommenting on taste-masking effects.

Japanese Patent Laid-open No. 76420/1977 and 24410/1983 describe amethod of preparing a porous tablet which comprises blending atablet-constituting composition with inert solvent, solidifying,compressing the resulting solid into tablets, and evaporating solvent byfreeze-drying. U.S. Pat. No. 5,501,861 discloses a method of preparing afast dissolving tablet comprising a water-soluble saccharide (such assugar, starch, lactose, sugar alcohol, or tetrose) and apharmacologically active ingredient, which comprises compressing theblended solid into tablets with a molding pressure of 5˜130 kg/cm² andevaporating the solvent by freeze-drying.

The above fast dissolving tablets are prepared by Zydis (from R. P.Scherer, England) freeze-drying. This method, however, suffer from highprocess cost and insufficient mechanical strength of the preparation.

Therefore, it is necessary to develop a preparation which offers apleasant taste and acceptable disintegration speed in an oral cavityafter dosage, and possesses a sufficient mechanical strength so as toprotect the preparation from destruction in the course of manufacture.

SUMMARY OF THE INVENTION

In order to solve the conventional problems, an object of the inventionis to provide an oral dosage form having taste-masking effects, rapiddisintegration rates, sufficient hardness to resist destruction duringthe course of manufacture and storage, and low cost.

To achieve the above objects, the invention provides a taste-maskingoral dosage form comprising a pharmaceutically active ingredient, and astarch, wherein the pharmaceutically active ingredient is packaged bythe starch to form a microparticle. The tablet further comprises ahydrophilic polymer, a surfactant, excipicents, or combinations thereof.

The tablet provided in the invention may be rapidly dissolved in an oralcavity, due to the hydrophilic polymer having strong water absorption,so that it can be advantageously used for treatment of diseases in theelderly or children. Additionally, the dissolution rate of the tablet isimproved by the surfactant in an oral cavity, particularly for veryslightly dissolved drugs.

Another object of the invention is to provide a method of preparing ataste-masking oral dosage form, comprising the following steps. A firstsolution comprising a pharmaceutically active ingredient and a starch isprovided. A second solution comprising a hydrophilic polymer and asurfactant is then provided. Subsequently, the first and secondsolutions are blended to form a plurality of microparticles by agranulating, and a compression-molding process is performed to form thetablet.

The tablet has an adequate hardness and rapid dissolving rate, due tothe specific granulation and additives thereof. More particularly, thebitter taste is wasted, because the pharmaceutically active ingredientis packaged by the starch. Additionally, the low-costcompression-molding process satisfies industry requirements.

A detailed description is given in the following embodiments withreference to the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention can be more fully understood by reading thesubsequent detailed description and examples with references made to theaccompanying drawings, wherein:

FIG. 1 is a flow chart of the granulating process of the invention.

FIG. 2 shows the microparticle structure prepared by the invention.

FIG. 3 is a flow chart of the compression-molding process of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1 and FIG. 2 illustrate the method of preparing the taste-maskingoral dosage form according to the embodiment of the invention. First,referring to FIG. 1, a first solution is provided in step S10. The firstsolution comprises solute comprising a pharmaceutically activeingredient and a starch and solvent comprising water or ethanol, whereinthe pharmaceutically active ingredient comprises any optional orallyadministrated drugs, and the starch comprises amylodextrin, hydroxyethylstarch, hydropropyl starch, carboxymethyl starch, acetylated starch, orphosphorylated starch. The uniform and viscous first solution isprepared by heating after blending.

The pharmaceutically active ingredient may be at least one memberselected from the group: (1) vitamins, for example, vitamin A, vitaminD, vitamin E, vitamin B₁, vitamin B₂, vitamin B₆, vitamin B₁₂, orvitamin C, minerals, for example, Ca, Mg, Fe, or protein, and amino acidor oligosaccharide and the like.

(2) antipyretic-analgesic-antiinflammatory agents, for example, aspirin,acetaminophen, ethenzamide, ibuprofen, diphenhydramine hydrochloride,dl-chorpheniramine maleate, dihydrocodeine phosphate, noscapine,methylephedrine hydrochloride, phenylpropanolamine hydrochloride,caffeine, serratiopeptidase, lysozyme chloride, tolfenamic acid,mefenamic acid, diclofenac sodium, flufenamic acid, salicylamide,aminopyrine, ketoprofen, indomethacin, bucolome, or pentazocine and thelike.

(3) antipsychotic drugs, for example, chlorpromazine, reserpine,chlordiazepoxide, diazepam, imipramine, maprotiline, amphetamine,estazolam, nitrazepam, diazepam, phenobarbital sodium, scopolaminehydrobromide, diphenhydramine hydrochloride, or papaverine hydrochlorideand the like.

(4) gastrointestinal function conditioning agents, for example,magnesium carbonate, sodium hydrogen carbonate, magnesiumaluminometasilicate, synthetic hydrotalcite, precipitated calciumcarbonate, or magnesium oxide and the like.

(5) antitussive-expectorants, for example, chloperastine hydrochloride,dextromethorphan hydrobromide, theophylline, potassiumguaiacolsulfonate, guaifenesin, oxytetracycline, triamcinoloneacetonide, chlorhexidine hydrochloride, or lidocaine and the like.

(6) antihistamines, for example, diphenhydramine hydrochloride,promethazine, isothipendyl hydrochloride, or dl-chlorpheniramine maleateand the like.

(7) cardiotonics, for example, etilefrine hydrochloride, procainamidehydrochloride, propranolol hydrochloride, pindolol, isosorbide,furosemide, delapril hydrochloride, captopril, hexamethonium bromide,hydralazine hydrochloride, labetalol hydrochloride, or methyldopa andthe like.

(8) vasoconstrictors, for example, phenylephrine hydrochloride,carbocromen hydrochloride, molsidomine, verapamil hydrochloride,cinnarizine, dehydrocholic acid, or trepibutone and the like.

(9) antibiotics, for example, cephems, penems, carbapenems, cefalexin,amoxicillin, pivmecillinam hydrochloride, or cefotiam dihydrochlorideand the like.

(10) chemotherapeutic drugs, for example, sulfamethizole orthiazosulfone and the like.

(11) antidiabetic agents, for example, tolbutamide or voglibose and thelike.

(12) drugs for osteoporosis, for example, ipriflavone and the like.

(13) skeletal muscle relaxants, for example, methocarvamol and the like.

Subsequently, a second solution is provided S12. The second solutioncomprises solute comprising a hydrophilic polymer and a surfactant andsolvent comprising water or ethanol, wherein the hydrophilic polymercomprises PEG, PVP, carbopol, polysaccharide, agar, MC, or HPMC, and thesurfactant comprises edible surfactants comprising phospholipid.

Next, the first and second solutions are blended in step S14 andcontinuously stirred to drop the temperature to lower than roomtemperature. Sediments comprising a plurality of co-crystalmicroparticles comprising the pharmaceutically active ingredient and thestarch may form after cooling, wherein the pharmaceutically activeingredient is packaged by the starch with the package percentageexceeding 95% to isolate the bitter taste, and the diameter of themicroparticle is about 150˜360 μm, as shown in FIG. 2. Subsequently, thesediments are filtered in step S16, dried in step S18 and sieved in stepS20. The granulating process comprises dry granulating, wet granulating,fluidized bed granulating, or spray granulating.

Next, referring to FIG. 3, microparticles and excipients are blended instep S22. The excipients comprises disintegrating agents, effervescentagents, sweeteners, and lubricants comprising saccharide, alcohol, andsugar alcohol, wherein saccharide comprises monosaccharide ordisaccharide, and sugar alcohol comprises mannitol, sorbitol, xylitol,or glycerol.

Subsequently, the mixture of microparticles and the excipients is sievedin step S24. After sieving, the mixture is compression-molded in stepS26 with a tabletting machine, for example, a High-Speed RotaryTabletting Machine.

The molding pressure of the High-Speed Rotary Tabletting Machine isabout 800˜1200 lb/cm², and preferably 1000 lb/cm². The molding speedthereof is about 15˜20 rpm, and preferably 16 rpm.

The taste-masking oral dosage form of the invention comprises apharmaceutically active ingredient in a proportion is generally about35˜45% by weight, a starch in a proportion is generally about 20˜30% byweight, a hydrophilic polymer in a proportion is generally about 2˜10%by weight, a surfactant in a proportion is generally about 2˜10% byweight, and excipients in a proportion are generally about 40˜50% byweight. Additionally, the porosity of the tablet is about 30˜70%, thedisintegration time (the time required to complete dissolution by salivain an oral cavity in a healthy adult male) thereof is less than 1 min,the hardness thereof is about 20˜50 NT, and the brittleness thereof isless than 2%. Specifically, the pharmaceutically active ingredient ispackaged with starch with the package percentage exceeding 95% toisolate the bitter taste.

EXAMPLE 1

A first solution comprising acetaminophen(antipyretic-analgesic-antiinflammatory agents), amylodextrin, and H₂Owas prepared as described in the following steps. First, 400 g ofacetaminophen and 84 g of amylodextrin were added into 1600 ml of H₂O,stirred, and the first solution was heated to 90° C.

Subsequently, a second solution comprising a PEG6000 (hydrophilicpolymer), lecithin (surfactant), and H₂O was prepared as the followingstep. First, 50 g of PEG6000 and 50 g of lecithin were added into 790 mlof heated H₂O at 70° C., and stirred to dissolve completely.

Next, a wet granulating process was performed, wherein the firstsolution was slowly added into the second solution, and continuouslystirred to drop the temperature to lower than room temperature duringblending. Sediments comprising a plurality of co-crystal microparticlescomprising the pharmaceutically active ingredient and the starch wasformed after cooling, wherein the pharmaceutically active ingredient ispackaged by the starch with the package percentage exceeding 95% toisolate the bitter taste, and the diameter of the microparticle is about150˜360 μm. Subsequently, sediments were filtered through the Buchnerfunnel, and dried in a dryer at 45° C. Then, sediments were siftedthrough a sieve with 400 μm diameter mesh.

Next, microparticles and excipients were blended with a V-shapedblender. The excipients comprises 250 g of lactose (disaccharide), 100 gof mannitol (sugar alcohol), and 100 g of crospovidone (disintegratingagents). Subsequently, the blend was sifted through a sieve with 200 μmdiameter mesh. Finally, 400 g of the blend was compression-molded toform a tablet with a High-Speed Rotary Tabletting Machine. The moldingpressure was about 1000 lb/cm², and the molding speed was about 15.9rpm.

In this example, 400 g of acetaminophen in a proportion is generallyabout 40% by weight, 50 g of amylodextrin in a proportion is generallyabout 5% by weight, 50 g of PEG6000 in a proportion is generally about5% by weight, 50 g of lecithin in a proportion is generally about 5% byweight, and 450 g of excipients comprising 250 g of lactose, 100 g ofmannitol, and 100 g of crospovidone in a proportion are generally about25% by weight.

EXAMPLE 2

To illustrate the effects of the invention in further detail, thefollowing characteristics of the tablets prepared in the foregoingexample was determined, comprising disintegration time, hardness, andbrittleness. The results are shown in Table 1.

(1) Disintegration Time

The disintegration time of each tablet was determined in accordance withthe disintegration test as described in the following. First, 37±2° C.,proper amount of water used as solvent was added into the container ofthe test machine (PHARMA TEST PTZ1 E type). Next, six tablets were addedinto the container, and the container was covered by a plastic cover.Subsequently, the test machine shook the container until the tabletswere disintegrated completely. The mean of the results of sixdeterminations of each pharmaceutically active ingredient was adoptedrespectively.

(2) Hardness

The hardness of each tablet was determined in accordance with thehardness test as described in the following. First, six tablets wereplaced on the hardness tester (SHIN KWANG SK-32060 type). Next, pressurewas applied from the long axis until the tablets were cracked. The meanof the results of six determinations of each pharmaceutically activeingredient was adopted respectively.

(3) Brittleness

The brittleness of each tablet was determined in accordance with thebrittleness test as described in the following. First, 6˜6.5 g ofsixteen tablets (380˜420 mg/per tablet) were placed on the sieve (10mesh). After dropped powders were removed, the precise sample weight(As) was measured. The sample was then added into the test machine(PHARMA TEST PTFE type), and the test machine spun at a speed of 25 rpmfor 100 turns. After the sample was taken out, all dropped powders wereremoved again. Finally, the precise sample weight (A₀) was measured. Asa result, Brittleness=(A₀/As)*100. The mean of the results of sixteendeterminations of each pharmaceutically active ingredient was adoptedrespectively. TABLE 1 Pharmaceutically Disintegration Hardnessbrittleness active ingredient time (sec) (NT) (%) acetaminophen 20 ± 524.9 ± 7.0 1.2

The results of Table 1 indicate that the disintegration time of the oraldosage forms of the present invention is less than 1 min, and thebrittleness thereof is less than 2%. Therefore, the elderly, children,or those with impaired swallowing ability are able to swallow thetablets, due to rapid disintegration and absorption in an oral cavity.Additionally, an adequate mechanical strength of 20˜50 NT is obtained,facilitating the packaging process in production lines.

While the invention has been described by way of example and in terms ofthe preferred embodiments, it is to be understood that the invention isnot limited to the disclosed embodiments. To the contrary, it isintended to cover various modifications and similar arrangements (aswould be apparent to those skilled in the art). Therefore, the scope ofthe appended claims should be accorded the broadest interpretation so asto encompass all such modifications and similar arrangements.

1. A taste-masking oral dosage form, comprising: a pharmaceutically active ingredient; and a starch, wherein the pharmaceutically active ingredient is packaged by the starch to form a microparticle;.
 2. The taste-masking oral dosage form as claimed in claim 1, wherein the pharmaceutically active ingredient comprises any optional orally administrated drugs.
 3. The taste-masking oral dosage form as claimed in claim 1, wherein the starch comprises amylodextrin, hydroxyethyl starch, hydropropyl starch, carboxymethyl starch, acetylated starch, or phosphorylated starch.
 4. The taste-masking oral dosage form as claimed in claim 1, wherein the package percentage exceeds 95%.
 5. The taste-masking oral dosage form as claimed in claim 1, wherein the microparticle is a co-crystal structure comprising the pharmaceutically active ingredient and the starch.
 6. The taste-masking oral dosage form as claimed in claim 1, wherein the diameter of the microparticle is about 150˜350 μm.
 7. The taste-masking oral dosage form as claimed in claim 1, wherein the tablet further comprises a hydrophilic polymer, a surfactant, excipients, or combinations thereof.
 8. The taste-masking oral dosage form as claimed in claim 7, wherein the hydrophilic polymer comprises PEG, PVP, carbopol, polysaccharide, agar, MC, or HPMC.
 9. The taste-masking oral dosage form as claimed in claim 7, wherein the surfactant comprises edible surfactants.
 10. The taste-masking oral dosage form as claimed in claim 7, wherein the surfactant comprises lecithin.
 11. The taste-masking oral dosage form as claimed in claim 7, wherein the excipient comprises disintegrating agents, effervescent, lubricants, or sweeteners.
 12. The taste-masking oral dosage form as claimed in claim 7, wherein the excipient comprises saccharide, alcohol, or sugar alcohol.
 13. The taste-masking oral dosage form as claimed in claim 12, wherein saccharide comprises monosaccharide or disaccharide.
 14. The taste-masking oral dosage form as claimed in claim 12, wherein sugar alcohol comprises mannitol, sorbitol, xylitol, or glycerol.
 15. The taste-masking oral dosage form as claimed in claim 1, wherein the pharmaceutically active ingredient in a proportion is generally about 5˜45% by weight.
 16. The taste-masking oral dosage form as claimed in claim 1, wherein the starch in a proportion is generally about 20˜30% by weight.
 17. The taste-masking oral dosage form as claimed in claim 7, wherein the hydrophilic polymer in a proportion is generally about 2˜10% by weight.
 18. The taste-masking oral dosage form as claimed in claim 7, wherein the surfactant in a proportion is generally about 2˜10% by weight.
 19. The taste-masking oral dosage form as claimed in claim 7, wherein the excipient in a proportion is generally about 40˜50% by weight.
 20. The taste-masking oral dosage form as claimed in claim 1, wherein the porosity of the tablet is about 30˜70%.
 21. The taste-masking oral dosage form as claimed in claim 1, wherein the brittleness of the tablet is less than 2%.
 22. A method of preparing a taste-masking oral dosage form, comprising: providing a first solution comprising a pharmaceutically active ingredient and a starch; providing a second solution comprising a hydrophilic polymer and a surfactant; blending the first and second solution to form a plurality of microparticles by a granulating process; and performing a compression-molding process to form the tablet.
 23. The method as claimed in claim 22, wherein the pharmaceutically active ingredient comprises any optional orally administrated drugs.
 24. The method as claimed in claim 22, wherein the starch comprises amylodextrin, hydroxyethyl starch, hydropropyl starch, carboxymethyl starch, acetylated starch, or phosphorylated starch.
 25. The method as claimed in claim 22, wherein the package percentage exceeds 95%.
 26. The method as claimed in claim 22, wherein the microparticle is a co-crystal structure comprising the pharmaceutically active ingredient and the starch.
 27. The method as claimed in claim 22, wherein the diameter of the microparticle is about 150˜350 μm.
 28. The method as claimed in claim 22, wherein the hydrophilic polymer comprises PEG, PVP, carbopol, polysaccharide, agar, MC, or HPMC.
 29. The method as claimed in claim 22, wherein the surfactant comprises edible surfactants.
 30. The method as claimed in claim 22, wherein the surfactant comprises lecithin.
 31. The method as claimed in claim 22, after the first and second solution is blended, further comprising adding excipients into the blended solution.
 32. The method as claimed in claim 31, wherein the excipient comprises disintegrating agents, effervescent, lubricants, or sweeteners.
 33. The method as claimed in claim 31, wherein the excipient comprises saccharide, alcohol, or sugar alcohol.
 34. The method as claimed in claim 33, wherein saccharide comprises monosaccharide or disaccharide.
 35. The method as claimed in claim 33, wherein sugar alcohol comprises mannitol, sorbitol, xylitol, or glycerol.
 36. The method as claimed in claim 22, wherein a molding pressure of the compression-molding is about 800˜1200 lb/cm².
 37. The method as claimed in claim 22, wherein a molding speed of the compression-molding is about 15˜20 rpm.
 38. The method as claimed in claim 22, wherein the pharmaceutically active ingredient in a proportion is generally about 5˜45% by weight.
 39. The method as claimed in claim 22, wherein the starch in a proportion is generally about 20˜30% by weight.
 40. The method as claimed in claim 22, wherein the hydrophilic polymer in a proportion is generally about 2˜10% by weight.
 41. The method as claimed in claim 22, wherein the surfactant in a proportion is generally about 2˜10% by weight.
 42. The method as claimed in claim 31, wherein the excipient in a proportion is generally about 40˜50% by weight.
 43. The method as claimed in claim 22, wherein the porosity of the tablet is about 30˜70%.
 44. The method as claimed in claim 22, wherein the brittleness of the tablet is less than 2%. 